(PHILADELPHIA- October 2, 2001)—By combining two techniques, an international team of scientists led by researchers at The Wistar Institute has derived the "quasi-atomic" structure of a common bacteriophage, a type of virus that infects bacteria. The results, reported in the October issue of the journal Structure, offer fresh insights into the ancient evolution of viruses and may help inform innovative strategies for countering infections by antibiotic-resistant bacteria.

The newly detailed structure confirms that the bacteriophage is remarkably similar in its structure to human adenoviruses, which infect the respiratory tract, despite pronounced genetic and other differences. The structural similarity between the viruses suggests to scientists that the structure they both exhibit - an icosahedron of 252 molecular building blocks - has been so useful for viral life that evolution has conserved it while defining disparate sets of genes to create it.

The bacteriophage studied, called PRD1, is also one of a family of viruses that infect a broad range of antibiotic-resistant bacterial strains, making them good candidates for possible therapeutic uses against those bacteria. PRD1 itself infects E. coli bacteria, one strain of which is responsible for tens of thousands of cases of food poisoning in the United States each year. The intimate knowledge of PRD1's structure provided by the current study may suggest ways to engineer viral modifications that would allow bacteriophages to serve as effective antibiotic agents.

"From a purely scientific perspective, we are intrigued by the striking structural similarities shared by these genetically distinct viruses," says structural biologist Roger M. Burnett, Ph.D., a professor at The Wistar Institute and corresponding author on the Structure study. "How could these viruses evolve to infect such different hosts as humans and bacteria while maintaining the same architecture? We speculate that this particular form of construction is flexible enough to accommodate genomes of very different sizes, which may have conferred an evolutionary advantage on these viruses.

"People are also interested in using bacteriophages to develop novel antibiotic strategies, particularly for possible use against antibiotic-resistant bacteria, and it may be that our findings will help inform that work."

The fact that the two virus types prey on widely divergent hosts - mammalian cells versus bacterial cells - deepens the relevance of evolutionary comparisons between adenoviruses and bacteriophages, Burnett says. The implication is that their shared evolutionary ancestry may date to a time before bacteria and eukaryotes - the branch of the tree of life that includes animals, plants, and fungi - went their different ways. This observation underscores the notion that the structure shared by the viruses was not only critical to their early success but proved adaptable enough to evolve along with their hosts.

The two imaging techniques used by the researchers to define the "quasi-atomic" structure of PRD1 are electron microscopy and X-ray crystallography. Computer modeling was then used to combine the information provided by the relatively low-resolution electron microscopy technique, which is able to image the entire virus particle, with the high-resolution capabilities of X-ray crystallography, able to provide atomic detail about the molecules that represent the building blocks of the overall viral structure

The lead author on the Structure study is Carmen San Martin, Ph.D., a member of Burnett's laboratory. Coauthors on the study are Felix de Haas, Ralph Heinkel, and Twan Rutten, of the European Molecular Biology Laboratory (EMBL), Heidelberg, Germany; Stephen D. Fuller of EMBL and University of Oxford, England; and Sarah J. Butcher and Dennis H. Bamford of the University of Helsinki, Finland.

Funding for the research was provided by the National Science Foundation, the National Institutes of Health, the Fannie E. Rippel Foundation, the Wellcome Trust, and the Academy of Finland.

The Wistar Institute is an independent nonprofit research institution dedicated to discovering the causes and cures for major diseases, including cancer and AIDS. The Institute is a National Cancer Institute-designated Cancer Center Ð one of the nation's first, funded continuously since 1968, and one of only 10 focused on basic research. Founded in 1892, Wistar was the first independent institution devoted to medical research and training in the nation. Since the Institute's inception, Wistar scientists have helped to improve world health through the development of vaccines against rabies, rubella, rotavirus, and cytomegalovirus and the identification of genes associated with breast, lung, prostate and other cancers.

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Featured Image: Horner Brass Microscope

The microscope in the image belonged to William E. Horner, M.D., a collaborator with Caspar Wistar, M.D., in the early 1800s.

Dr. Horner, a lecturer at the University of Pennsylvania, was a pioneer of the use of microscopes in anatomical and medical research. He authored Special Anatomy and Histology, a seminal text on the subject.